Sterile drug products provide a number of benefits, both medically and economically. The medical ramifications requiring sterile drug preparations are obvious in that the use of non-sterile preparations may subject the patient to an unnecessary risk of secondary infection from the contaminating microbe, a microbe that is at least resistant to the drugs of the preparation. Furthermore, even if the contaminant is innocuous, the growth can result in loss of active drug products per se with possible concomitant generation of toxic by-products. Economically, contaminated drug products have a shortened shelf life, which requires increased production expenses to replace product on a more frequent basis.
Methods are needed for the preparation of sterile products for patient use. However, the problem associated with many sterilization procedures is that the process often results in unfavorable changes in the drug profile. These changes in the drug profile can range from loss of activity, to increased degradation products being created, or possible alteration of the chemical or physical characteristics of the compound sterilized. These problems are especially pronounced when glucocorticosteroids are sterilized.
Sterilization of materials relies on the input of sufficient energy to be lethal to any potential microbial contamination. Numerous methods including heat, radiation, and chemicals have been proposed for the sterilization of glucocorticosteroids. However, to date these methods often result in the excess production of degradants or a loss of activity for the glucocorticosteroid being sterilized. Additionally, as in the case of glucocorticosteroid suspension formulations for metered dose inhalation, the commonly used sterilization procedures often results in unacceptable changes to drug particle size.
Chemical sterilization, for the most part, has been based on exposure to toxic compounds, for example, ethylene oxide. However, when used to sterilize glucocorticosteroids, ethylene oxide has been found to leave residual amounts of ethylene oxide in the drug preparation. Ethylene oxide is toxic and the residual levels are often above the pharmaceutically acceptable limits as set by most regulatory agencies.
Irradiation based sterilization is known and has been recommended for glucocorticosteroids (see Ilium and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174). However, significant degradation has been reported when irradiation has been used to sterilize micronized glucocorticosteroids.
WO 02/41925 to Breath Limited purportedly discloses a rapid method, similar to pasteurization, for the sterilization of compositions. This method entails pumping the composition to be sterilized through stainless steel pipes and rapidly raising the temperature of the composition to about 130-145° C. for about 2-20 seconds, subsequently followed by rapid cooling in seconds to ambient conditions.
U.S. Pat. No. 3,962,430 to O'Neil discloses a method for the production of sterile isotonic solutions of medicinal agents. The method comprises adding the medicinal agent to a saturated solution of sodium chloride in water at 100° C. The drug/saturated sodium chloride solution is then heated to 100-130° C. This method, which purportedly is based on the theory that the sodium chloride ions tie up free water, thereby preventing hydrolytic degradation, is not suitable for suspensions of fine particles of glucocorticosteroids intended for inhalation, as the procedure produces unfavorable changes in the size of the particles. Additionally, the procedure can result in bridge formation between drug particles producing large aggregates, which do not break up on administration.
U.S. Pat. No. 6,464,958 to Bernini, et al., discloses that heat sterilization of suspension formulations for many drugs produces unfavorable changes in the drug profile including, for example, aggregation of drug particles. Some of the unfavorable changes are correctable. For example, aggregates formed during heat sterilization could be re-treated to brake up the aggregates into smaller sized particles suitable for nasal administration. However, some unfavorable changes cannot be corrected, as in the case of beclomethasone dipropionate. For example, Bernini reports that beclomethasone suspensions sterilized by a wet steam process similar to that reported in U.S. Pat. No. 3,962,430 supra, undergo a marked decrease in active ingredient content (about 8-9%), with a concomitant increase in degradation products (about 10-11%).
Karlsson, et al., in U.S. Pat. No. 6,392,036 discloses a method for the dry heat sterilization of powdered glucocorticosteroids that can then be used for drug formulations.
Methods are needed to sterilize suspension glucocorticosteroid pharmaceutical compositions. Sterilization should occur without producing pharmaceutically unacceptable changes to drug particle size while concomitantly minimizing degradation product production and loss of drug activity. Ideally, for sterile pharmaceutical products, the last stage of preparation of the product should be the sterilization process, thereby minimizing the potential for contamination during manufacture.